Ann Pediatr Endocrinol Metab.  2017 Sep;22(3):203-207. 10.6065/apem.2017.22.3.203.

An atypical case of Noonan syndrome with KRAS mutation diagnosed by targeted exome sequencing

• Kim J
• Cho SY
• Yang A
• Jang JH
• Choi Y
• Lee JE
• Jin DK

• KMID: 2396141
• DOI: http://doi.org/10.6065/apem.2017.22.3.203

Abstract

Noonan syndrome (NS) is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES) is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

Keyword

Noonan syndrome; Targeted exome sequencing; Genetic heterogeneity; KRAS

MeSH Terms

Congenital Abnormalities
Cryptorchidism
Diagnosis
Exome*
Genetic Counseling
Genetic Heterogeneity
Germ-Line Mutation
Heart Defects, Congenital
Humans
Intellectual Disability
Male
Methods
Molecular Biology
Noonan Syndrome*
Phenotype
Protein Kinases
Puberty, Delayed
Signal Transduction
Thoracic Wall
Thorax
Wills
Protein Kinases

Figure

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  Fig. 1. Growth curve of patient with Noonan syndrome and X-ray of the left hand of patient at 16 years of age. Height (A), weight (B), and X-ray of left hand (C). The growth curve shows the severe growth retardation of the patient. At the age of 6 years, he was treated with growth hormone for 6 months. His bone maturation at age 16 was delayed (the standard bone age is 10 years for a male according to the Greulich and Pyle atlas).

• 

  Fig. 2. Sanger sequencing confirmation of heterozygous mutation of KRAS. Heterozygous de novo mutation of c.458A > T (p.D153V) in exon 5 of KRAS was found by targeted exome sequencing and was confirmed by Sanger sequencing analysis (reference sequence: NM_004985.4).

Reference

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